1. Field of the Invention
The present invention relates to a process for the preparation of pyrrolizine derivatives, and more particularly to a process for the preparation of 7a-aminomethyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine and salts thereof, as well as a process for the preparation of 7a-cyano-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine and salts thereof, as an intermediate for synthesizing said 7a-aminomethyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine.
2. Related Arts
7a-Aminomethyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine and 7a-cyano-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine shown by the following formulae (1-B and 1-A) have been known as useful compounds for preparing various pharmaceutical and agricultural medicines, since those have an alkaroid skeletone therein. ##STR2##
Further, each of the compounds can also be employed as the raw material for synthesizing organo-platinum complexes [Jap. Pat. No. Sho 61-229893(A)], 2-oxopyrrolidine compounds and salts thereof [Jap. Pat. No. Sho 61-254587(A)] as well as cephalosporin derivatives [Jap. Pat. No. Sho 62-16487(A)].
As far as the synthesis of 7a-aminomethyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine is concerned, hitherto, only one method has been known, wherein 7a-cyano-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine is reduced with use of lithium aluminum hydride [Miyano et al. "Abstract on the 97th Annual Lecture of the Pharmaceutical Society of Japan", page 223 (1978)]. In this case, the raw material of 7-cyano-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine has been prepared by reacting .gamma.-butyrolactone with KOCN, thermally treating the resulting .gamma.-(N-2-pyrrolidinonyl)butyric acid in the presence of soda lime, reacting the resulting 2,3,5,6-tetrahydro-1H-pyrrolizine with perchloric acid, and reacting the resulting 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate with potassium cyanide [Miyano et al. "Synthesis", page 701 (1978)]. Such a process has also been proposed for preparing said .gamma.-(N-2-pyrrolidinonyl)butyric that .gamma.-butyrolactone is added to a reaction mixture of 2-pyrrolidone and sodium [Miyano et al. "J. Heterocyclic Chem.", Vol. 19, page 1455 (1982)].
Further, it has been known as the process for the preparation of 7a-substituted-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine derivatives that said 1,2,3,5,6,7-hexahydropyrrolizinium perchlorate is reacted with one of various nucleophilic reagents, or that the cyano group in said 7a-cyano-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine is chemically modified or changed.
The following is summary of said related arts, shown by chemical formulae. ##STR3##
The conventional process for preparing 7a-aminomethyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine as referred to, however, has disadvantages as stated below.
The first step of that .gamma.-butyrolactone is reacted with KOCN to synthesize .gamma.-(N-2-pyrrolidinonyl)butyric acid has problems in that a relatively high temperature (about 200.degree. C.) is required for the reaction, and that yield of the product is somewhat low (about 40%). Such a process developed as another or separate method that after the reaction between 2-pyrrolidone and sodium, .gamma.-butyrolactone is added to synthesize .gamma.-(N-2-pyrrolidinonyl)-butyric acid has a problem in that there is possibility of causing an explosion or the like abnormal reaction.
The second step of that .gamma.-(N-2-pyrrolidinonyl)butyric acid is thermally treated in the presence of sodalime to synthesize 2,3,5,6-tetrahydro-1H-pyrrolizine has problems in that a relatively high temperature (about 250.degree.-300.degree. C.) is required for the reaction, and that the resulting compound has a relatively low stability.
Further, the final step of that 7a-cyano-2,3,5,6-tetrahydro-1H-pyrrolizine is reduced to synthesize 7a-aminomethyl-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine has also problems of that an expensive lithium aluminum hydride is required as the reduction reagent, and that the reaction should be carried out in an anhydrous solvent.
Each of the processes, wherein 1,2,3,5,6,7-hexahydro-pyrrolizinium perchlorate is reacted with the nucleophilic reagent, or cyano group in 7a-cyano-2,3,5,6,7,7a-hexahydro-1H-pyrrolizine is chemically modified has the disadvantage of that a production of its starting material is difficult, as referred to.